Antibacterial quinoline derivatives

Abstract

The present invention relates to novel substituted quinoline derivatives according to the general formula (Ia) or formula (Ib): including any stereochemically isomeric form thereof, a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvateas thereof. The claimed compounds are useful for the treatment of a bacterial infection. Also claimed is a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the claimed compounds, the use of the claimed compounds or compositions for the manufacture of a medicament for the treatment of a bacterial infection and a process for preparing the claimed compounds.

1 . A compound of formula (Ia) or (Ib) 
       
         
           
           
               
               
           
         
         including any stereochemically isomeric form thereof, wherein 
         p is an integer equal to 1, 2, 3 or 4; 
         q is an integer equal to zero, 1, 2, 3 or 4; 
         R 1  is hydrogen, cyano, formyl, carboxyl, halo, alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloalkyl, hydroxy, alkyloxy, alkylthio, alkylthioalkyl, —C═N—OR 11 , amino, mono or di(alkyl)amino, aminoalkyl, mono or di(alkyl)aminoalkyl, alkylcarbonylaminoalkyl, aminocarbonyl, mono or di(alkyl)aminocarbonyl, arylalkyl, arylcarbonyl, R 5a R 4a Nalkyl, di(aryl)alkyl, aryl, R 5a R 4a N—, R 5a R 4a N—C(═O)—, or Het; 
         R 2  is hydrogen, alkyloxy, aryl, aryloxy, hydroxy, mercapto, alkyloxyalkyloxy, alkylthio, mono or di(alkyl)amino, pyrrolidino or a radical of formula 
       
       
         
           
           
               
               
           
         
       
       wherein Y is CH 2 , O, S, NH or N-alkyl;
 R 3  is alkyl, arylalkyl, aryl-O-alkyl, aryl-alkyl-O-alkyl, aryl, aryl-aryl, Het, Het-alkyl, Het-O-alkyl, Het-alkyl-O-alkyl or 
 
       
         
           
           
               
               
           
         
         R 4  and R 5  each independently is hydrogen; alkyl; alkyloxyalkyl; arylalkyl; Het-alkyl; mono- or dialkylaminoalkyl; bicyclo[2.2.1]heptyl; Het; aryl; or —C(═NH)—NH 2 ; or 
         R 4  and R 5  together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 1,1-dioxide-thiomorpholinyl, azetidinyl, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2,5-diazabicyclo[2.2.1]heptyl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical optionally substituted with 1, 2, 3 or 4 substituents, each substituent independently selected from alkyl, haloalkyl, alkylcarbonyl, halo, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, alkylthio, alkylthioalkyl, aryl, pyridyl, pyrimidinyl, piperidinyl optionally substituted with alkyl or pyrrolidinyl optionally substituted with arylalkyl; 
         R 4a  and R 5a  together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical optionally substituted with 1, 2, 3 or 4 substituents, each substituent independently selected from alkyl, haloalkyl, halo, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkylthioalkyl, aryl, pyridyl or pyrimidinyl; 
         R 7  is hydrogen, halo, alkyl, aryl or Het; 
         R 8  is hydrogen or alkyl; 
         R 9  is oxo; or 
         R 8  and R 9  together form the radical —CH═CH—N═; 
         R 11  is hydrogen or alkyl; 
         aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each being optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl,
 C 2-6 alkenyl optionally substituted with phenyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or dialkylaminocarbonyl; 
 
         Het is a monocyclic heterocycle selected from N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl,
 2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each monocyclic and bicyclic heterocycle being optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, hydroxy, alkyl or alkyloxy; 
 
         a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvateas thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein
 R 3  is alkyl, arylalkyl, aryl-O-alkyl, aryl-alkyl-O-alkyl, aryl, Het, Het-alkyl, Het-O-alkyl, Het-alkyl-O-alkyl or 
 
       
         
           
           
               
               
           
         
         R 4  and R 5  each independently is hydrogen; alkyl; alkyloxyalkyl; arylalkyl; Het-alkyl; mono- or dialkylaminoalkyl; Het; aryl; or —C(═NH)—NH 2 ; or 
         R 4  and R 5  together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidino, piperidino, piperazino, morpholino, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, hexahydro-1H-azepinyl, hexahydro-1H-1,4-diazepinyl, hexahydro-1,4-oxazepinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2,5-diazabicyclo[2.2.1]heptyl, pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, each radical optionally substituted with 1, 2, 3 or 4 substituents, each substituent independently selected from alkyl, haloalkyl, alkylcarbonyl, halo, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkylthioalkyl, aryl, pyridyl, pyrimidinyl, piperidinyl or pyrrolidinyl optionally substituted with arylalkyl; 
         aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each being optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or dialkylaminocarbonyl. 
       
     
     
         3 . A compound according to  claim 1  or  2  wherein alkyl represents C 1-6 alkyl. 
     
     
         4 . A compound according to  claim 1  wherein R 1  is halo, Het or aryl. 
     
     
         5 . A compound according to  claim 4  wherein R 1  is halo. 
     
     
         6 . A compound according to  claim 1  wherein p is equal to 1. 
     
     
         7 . A compound according to  claim 1  wherein R 2  is C 1-6 alkyloxy. 
     
     
         8 . A compound according to  claim 1  wherein R 3  is aryl. 
     
     
         9 . A compound according to  claim 1  wherein q is equal to 2, 3 or 4. 
     
     
         10 . A compound according to  claim 1  wherein R 4  and R 5  represent C 1-6 alkyl. 
     
     
         11 . A compound according to  claim 1  wherein R 7  is hydrogen. 
     
     
         12 . A compound according to  claim 1  wherein the compound is a compound of formula (Ia). 
     
     
         13 . A compound according to  claim 12  wherein R 1  is halo; R 2  is C 1-6 alkyloxy; R 3  is aryl; R 4  and R 5  are C 1-6 alkyl; R 7  is hydrogen; q is 2, 3 or 4; and p is 1. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in  claim 1 . 
     
     
         17 . Use A method of treating a patient for a bacterial infection comprising administering to said patient a therapeutically effective amount of a compound according to of  claim 1 . 
     
     
         18 . A method according to  claim 17  wherein the bacterial infection is an infection with a gram-positive bacterium. 
     
     
         19 . A method according to  claim 17  wherein the gram-positive bacterium is  Streptococcus pneumoniae.    
     
     
         20 . A method according to  claim 17  wherein the gram-positive bacterium is  Staphylococcus aureus.    
     
     
         21 . A process to prepare a compound according to  claim 1  characterized by reacting an intermediate of formula (IIa) or (IIb) with an intermediate of formula (III) according to the following reaction scheme 
       
         
           
           
               
               
           
         
         using nBuLi in a mixture of a suitable base and a suitable solvent, wherein all variables are defined as in  claim 1 ; 
         or, if desired, converting compounds of formula (Ia) or (Ib) into each other following art-known transformations, and further, if desired, converting the compounds of formula (Ia) or (Ib), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing stereochemically isomeric forms, quaternary amines or N-oxide forms thereof. 
       
     
     
         22 . A combination of (a) a compound according to  claim 1 , and (b) one or more other antibacterial agents. 
     
     
         23 . A product containing (a) a compound according to  claim 1 , and (b) one or more other antibacterial agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.